Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments

ABSTRACT

Enantiomerically pure compounds of general formula 1 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1 , R 2 , R 3 , R 4 , and X −  may have the meanings given in the claims and in the specification, processes for preparing them and the use thereof as pharmaceutical compositions, particularly as pharmaceutical compositions for the treatment of respiratory complaints.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/128,032, filedMay 12, 2005, now U.S. Pat. No. ______ which claimed benefit of U.S.Ser. No. 60/578,567, filed Jun. 10, 2004, and claimed priority to GermanApplication No. DE 10 2004 024454.4, filed May 14, 2004, each of whichis hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to enantiomerically pure compounds ofgeneral formula 1

wherein the groups R¹, R², R³, R⁴, and X⁻ may have the meanings given inthe claims and in the specification, processes for preparing them andthe use thereof as pharmaceutical compositions, particularly aspharmaceutical compositions for the treatment of respiratory complaints.

BACKGROUND OF THE INVENTION

Betamimetics (β-adrenergic substances) are known from the prior art. Forexample reference may be made in this respect to the disclosure of U.S.Pat. No. 4,460,581, which proposes betamimetics for the treatment of arange of diseases.

For drug treatment of diseases it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewell-being of the patient to a high degree.

It is particularly desirable to prepare a pharmaceutical compositionwhich can be used therapeutically by administration once a day (singledose). The use of a drug once a day has the advantage that the patientcan become accustomed relatively quickly to regularly taking the drug atcertain times of the day.

The aim of the present invention is to provide betamimetics which on theone hand confer a therapeutic benefit in the treatment of respiratorycomplaints and are also characterized by a longer duration of activityand can thus be used to prepare pharmaceutical compositions with alonger duration of activity. A particular aim of the invention is toprepare betamimetics which, by virtue of their long-lasting effect, canbe used to prepare a drug for administration once a day for treatingrespiratory complaints. A further objective of the invention, apart fromthose mentioned above, is to prepare betamimetics which are not onlyexceptionally potent but are also characterized by a high degree ofselectivity with respect to the β₂-adrenoceptor.

A further aim of the present invention is to prepare betamimetics whichby virtue of their physicochemical properties are particularly suitablefor preparing pharmaceutical formulations for use by inhalation. Thepresent invention sets out in particular to prepare betamimetics which,in addition to the abovementioned properties, are particularly suitablefor preparing inhalable powders and suspension aerosols.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that these objectives are achieved withcompounds of general formula 1.

The present invention relates to enantiomerically pure compounds ofgeneral formula 1

wherein

-   R¹ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy or halogen;-   R² denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy or halogen;-   R³ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, halogen, OH,    —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-COO—C₁-C₄-alkyl;-   R⁴ denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy or halogen; and-   X⁻ denotes an anion with a single negative charge, preferably an    anion with a single negative charge selected from among chloride,    bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate,    maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate,    fumarate, tartrate, oxalate, succinate, benzoate and    p-toluenesulfonate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Preferred are enantiomerically pure compounds of general formula 1,wherein

-   R¹ denotes hydrogen or halogen;-   R² denotes hydrogen or halogen;-   R³ denotes hydrogen, C₁-C₄-alkoxy or halogen;-   R⁴ denotes hydrogen or halogen; and-   X⁻ denotes an anion with a single negative charge, preferably an    anion with a single negative charge selected from among chloride,    bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate,    maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate,    fumarate, tartrate, oxalate, succinate, benzoate and    p-toluenesulfonate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Preferred are enantiomerically pure compounds of general formula 1,wherein

-   R¹ denotes hydrogen, fluorine or chlorine, preferably hydrogen or    fluorine;-   R² denotes hydrogen, fluorine or chlorine, preferably hydrogen or    fluorine;-   R³ denotes hydrogen, methoxy, ethoxy, fluorine or chlorine,    preferably hydrogen, methoxy, ethoxy or fluorine;-   R⁴ denotes hydrogen, fluorine or chlorine, preferably hydrogen or    fluorine; and-   X⁻ an anion with a single negative charge, preferably an anion with    a single negative charge selected from among chloride, bromide,    iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, benzoate and p-toluenesulfonate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Preferred are enantiomerically pure compounds of general formula 1,wherein

-   R¹ denotes hydrogen or fluorine;-   R² denotes hydrogen;-   R³ denotes methoxy, ethoxy or fluorine;-   R⁴ denotes hydrogen; and-   X⁻ denotes an anion with a single negative charge selected from    among chloride, bromide, sulfate, methanesulfonate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate and succinate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Of equal importance according to the invention are also enantiomericallypure compounds of general formula 1, wherein:

-   R¹ denotes hydrogen;-   R² denotes hydrogen, fluorine or chlorine, preferably hydrogen or    fluorine;-   R³ denotes hydrogen;-   R⁴ denotes hydrogen, fluorine or chlorine, preferably hydrogen or    fluorine; and-   X⁻ denotes an anion with a single negative charge selected from    among chloride, bromide, sulfate, methanesulfonate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate and succinate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Also preferred are enantiomerically pure compounds of general formula 1,wherein

-   X⁻ denotes an anion with a single negative charge selected from    among chloride, methanesulfonate, maleate, acetate, citrate,    salicylate, trifluoroacetate, fumarate, and succinate, preferably    chloride, maleate, salicylate, fumarate, and succinate, particularly    preferably chloride;    and R¹, R², R³ and R⁴ may have the meanings given above, optionally    in the form of the tautomers, mixtures of the tautomers, hydrates or    solvates thereof.

Also particularly preferred are compounds of general formula 1 which areselected from among:

-   6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one    hydrochloride;-   8-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hydrochloride;-   8-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hydrochloride;-   8-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hydrochloride;-   8-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hydrochloride;-   6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one    maleate;-   6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one    salicylate;-   6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one    succinate;-   6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one    fumarate;-   8-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate;-   8-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    salicylate;-   8-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    succinate;-   8-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    fumarate;-   8-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate;-   8-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    salicylate;-   8-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    succinate;-   8-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    fumarate;-   8-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate;-   8-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    salicylate;-   8-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    succinate;-   8-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    fumarate;-   8-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate;-   8-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    salicylate;-   8-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    succinate and-   8-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    fumarate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Also particularly preferred are enantiomerically pure compounds ofgeneral formula 1, wherein R¹, R², R³, R⁴ and X⁻ have the meanings givenabove, in crystalline form, optionally in the form of their crystallinetautomers, crystalline hydrates or crystalline solvates. Particularlypreferred are enantiomerically pure, crystalline compounds of generalformula 1 wherein R¹, R², R³, R⁴ and X⁻ have the meanings given above,optionally in the form of their crystalline tautomers, crystallinehydrates or crystalline solvates, which are further characterized inthat they are crystalline compounds which are present in only a singlecrystal modification.

By the expression “a single crystal modification” are meant crystallinecompounds of formula 1 which are not a mixture of any polymorphiccrystal modifications that may exist.

The compounds of formula 1 according to the invention are characterizedby their versatility of use in the therapeutic field. Particular mentionshould be made according to the invention of those possible applicationsfor which the compounds according to the invention of formula 1 arepreferably used on account of their pharmaceutical efficacy asbetamimetics.

In another aspect the present invention therefore relates to theabove-mentioned enantiomerically pure compounds of formula 1 aspharmaceutical compositions. The present invention also relates to theuse of the above-mentioned compounds of general formula 1 for preparinga pharmaceutical composition for the treatment of respiratorycomplaints.

The present invention preferably relates to the use of theabove-mentioned compounds of general formula 1 for preparing apharmaceutical composition for the treatment of respiratory complaintswhich are selected from among obstructive pulmonary diseases of variousorigins, pulmonary emphysema of various origins, restrictive pulmonarydiseases, interstitial pulmonary diseases, cystic fibrosis, bronchitisof various origins, bronchiectasis, ARDS (adult respiratory distresssyndrome) and all forms of pulmonary edema.

It is preferable to use compounds of general formula 1 for preparing apharmaceutical composition for the treatment of obstructive pulmonarydiseases which are selected from among COPD (chronic obstructivepulmonary disease), bronchial asthma, pediatric asthma, severe asthma,acute asthma attacks and chronic bronchitis, while it is particularlypreferable according to the invention to use them for preparing apharmaceutical composition for the treatment of bronchial asthma.

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of pulmonaryemphysemas that have their origin in COPD (chronic obstructive pulmonarydisease) or α1-proteinase inhibitor deficiency.

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of restrictivepulmonary diseases, which are selected from among allergic alveolitis,restrictive pulmonary diseases triggered by work-related noxioussubstances, such as asbestosis or silicosis, and restriction caused bylung tumors, such as for example lymphangiosis carcinomatosa,bronchoalveolar carcinoma and lymphomas.

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of interstitialpulmonary diseases which are selected from among pneumonia caused byinfections, such as for example infection by viruses, bacteria, fungi,protozoa, helminths or other pathogens, pneumonitis caused by variousfactors, such as for example aspiration and left heart insufficiency,radiation-induced pneumonitis or fibrosis, collagenoses, such as forexample lupus erythematodes, systemic sclerodermy or sarcoidosis,granulomatoses, such as for example Boeck's disease, idiopathicinterstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of cysticfibrosis or mucoviscidosis.

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of bronchitis,such as for example bronchitis caused by bacterial or viral infection,allergic bronchitis and toxic bronchitis.

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment ofbronchiectasis.

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of ARDS (adultrespiratory distress syndrome).

It is also preferable to use compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of pulmonaryedemas, for example toxic pulmonary edema after aspiration or inhalationof toxic substances and foreign substances.

Particularly preferably, the present invention relates to the use of thecompounds of formula 1 for preparing a pharmaceutical composition forthe treatment of asthma or COPD. Also of particular importance is theabove-mentioned use of compounds of formula 1 for preparing apharmaceutical composition for once-a-day treatment of inflammatory andobstructive respiratory complaints, particularly for the once-a-daytreatment of asthma or COPD.

Moreover the present invention relates to a method of treating theabovementioned diseases, characterized in that one or more of theabove-mentioned compounds of general formula 1 are administered intherapeutically effective amounts. The present invention preferablyrelates to methods of treating asthma or COPD, characterized in that oneor more of the above-mentioned compounds of general formula 1 areadministered once a day in therapeutically effective amounts.

Unless otherwise stated, the alkyl groups are straight-chained orbranched alkyl groups having 1 to 4 carbon atoms. The following arementioned by way of example: methyl, ethyl, propyl or butyl. In somecases the abbreviations Me, Et, Prop or Bu are used to denote the groupsmethyl, ethyl, propyl or butyl. Unless otherwise stated, the definitionspropyl and butyl include all the possible isomeric forms of the groupsin question. Thus, for example, propyl includes n-propyl and isopropyl,butyl includes isobutyl, sec-butyl and tert-butyl, etc.

Unless otherwise stated, the alkylene groups are branched and unbrancheddouble-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include:methylene, ethylene, n-propylene or n-butylene.

Unless otherwise stated, the term alkyloxy groups (or —O-alkyl groups)denotes branched and unbranched alkyl groups having 1 to 4 carbon atomswhich are linked via an oxygen atom. Examples of these include:methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeO—,EtO—, PropO— or BuO— are used in some cases to denote the groupsmethyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, thedefinitions propyloxy and butyloxy include all possible isomeric formsof the groups in question. Thus, for example, propyloxy includesn-propyloxy and isopropyloxy, butyloxy includes isobutyloxy,sec-butyloxy and tert-butyloxy, etc. In some cases, within the scope ofthe present invention, the term alkoxy is used instead of the termalkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy mayalso be used to denote the groups methyloxy, ethyloxy, propyloxy orbutyloxy.

Within the scope of the present invention halogen denotes fluorine,chlorine, bromine or iodine. Unless otherwise stated, fluorine, chlorineand bromine are the preferred halogens.

The term enantiomerically pure within the scope of the present inventiondescribes compounds of formula 1 which are present with an enantiomericpurity of at least 85% ee, preferably at least 90% ee, particularlypreferably ≧95% ee. The term ee (enantiomeric excess) is known in theart and describes the optical purity of chiral compounds.

The preparation of the compounds according to the invention may becarried out according to the method outlined in Diagram 1.

In the compounds of formulae 2 to 5 and 7 specified in Diagram 1 thegroup OPG denotes a hydroxyl function protected by a protective group(PG). With regard to the choice of suitable protective groups for thehydroxyl group reference is hereby made to the prior art as laid out forexample in Protective Groups in Organic Synthesis, T. W. Greene and P.G. M. Wuts, John Wiley & Sons Inc, Third Edition, 1999.

Preferably OPG denotes a group which is selected from among—O—C₁-C₄-alkyl, —O-benzyl, or —O—CO—C₁-C₄-alkyl, preferably —O-methyl,—O-benzyl, or —O-acetyl, particularly preferably —O-methyl or —O-benzyl,particularly preferably —O-benzyl.

In the compounds of formulae 3 and 4 specified in Diagram 1 the group Ldenotes a leaving group. Preferably L denotes a leaving group which isselected from among chlorine, bromine, iodine, methanesulfonate,trifluoromethanesulfonate and p-toluenesulfonate, preferably chlorine orbromine, particularly preferably chlorine.

In the compounds of formulae 6 and 7 specified in Diagram 1, the groupsR¹, R², R³, and R⁴ may have the meanings given above.

Starting from 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one (2) thecompounds of general formula 3 are prepared in the manner known in theart. The compound of formula 3 is then enantioselectively converted, inthe presence of a chiral transition metal catalyst, into the chiralalcohol of general formula 4, which is then reacted under suitableconditions to form the chiral oxirane of formula 5. Methods of carryingout the enantioselective synthesis of oxiranes are known in the art (cffor example Hamada et al., Org. Letters 2002, 4, 4373-4376). By reactingthe oxiranes 5 with the amines of formula 6 the compounds of formula 7are obtained, which can be converted into the salts of formula 1 afterthe protective group (PG) has been cleaved.

In view of their central importance as intermediate products in thesynthesis of the compounds of formula 1 according to the invention, inanother aspect the present invention relates to the compounds of formula5 per se

wherein OPG denotes a hydroxyl function protected by a protective groupPG, preferably a group which is selected from —O—C₁-C₄-alkyl, —O-benzyl,or —O—CO—C₁-C₄-alkyl, preferably —O-methyl, —O-benzyl, or —O-acetyl,particularly preferably —O-methyl or —O-benzyl, particularly preferably—O-benzyl.

In another aspect the present invention relates to the use of a compoundof formula 5, wherein OPG may have the meanings given above, as startingcompound for preparing a compound of formula 1, wherein the groups R¹,R², R³, R⁴ and X⁻ may have the meanings given above. In another aspectthe present invention relates to the use of a compound of formula 5,wherein OPG may have the meanings given above, for preparing a compoundof formula 1, wherein the groups R¹, R², R³, and X⁻ may have themeanings given above.

In the light of their central importance as intermediate products in thesynthesis of the compounds of formula 1 according to the invention, inanother aspect the present invention relates to the compounds of formula7 per se

wherein OPG denotes a hydroxyl function protected by a protective groupPG, preferably a group which is selected from —O—C₁-C₄-alkyl, —O-benzylor —O—CO—C₁-C₄-alkyl, preferably —O-methyl, —O-benzyl or —O-acetyl,particularly preferably —O-methyl or —O-benzyl, particularly preferably—O-benzyl, and wherein the groups R¹, R², R³ and R⁴ may have themeanings given above.

In another aspect the present invention relates to the use of a compoundof formula 7, wherein OPG, R¹, R², R³ and R⁴ may have the meanings givenabove, as an intermediate product in the preparation of a compound offormula 1, wherein the groups R¹, R², R³, R⁴ and X⁻ may have themeanings given above. In another aspect the present invention relates tothe use of a compound of formula 7, wherein OPG, R¹, R², R³ and R⁴ mayhave the meanings given above, for preparing a compound of formula 1,wherein the groups R¹, R², R³, R⁴ and X⁻ may have the meanings givenabove.

The enantiomerically pure compounds of formula 1 may optionally also beobtained by the method illustrated in Diagram 2.

The compound of formula 7 which may be obtained according to Diagram 1may then optionally be converted first of all into the free bases offormula 1′, while the groups R¹, R², R³ and R⁴ may have the meaningsgiven above. The free bases of formula 1′ are converted by reaction witha suitable acid H—X into the compounds of formula 1, which may beobtained in crystalline form by precipitation in a suitable solvent, forexample in an alcohol, preferably in an alcohol selected fromisopropanol, ethanol or methanol, optionally mixtures thereof, such asfor example isopropanol/methanol mixtures.

In the light of their central importance as possible intermediateproducts in the synthesis of the compounds of formula 1 according to theinvention, in another aspect the present invention relates to thecompounds of formula 1′ per se

wherein the groups R¹, R², R³ and R⁴ may have the meanings given above.

In another aspect the present invention relates to the use of a compoundof formula 1′, wherein R¹, R², R³ and R⁴ may have the meanings givenabove, as an intermediate product in the preparation of a compound offormula 1, wherein the groups R¹, R², R³, R⁴ and X⁻ may have themeanings given above.

In another aspect the present invention relates to the use of a compoundof formula 1′, wherein R¹, R², R³ and R⁴ may have the meanings givenabove, for preparing a compound of formula 1, wherein the groups R¹, R²,R³, R⁴ and X⁻ may have the meanings given above.

The reactions carried out are described in an exemplary capacity in thefollowing experimental section of this patent application. The examplesof synthesis described below serve to illustrate new compounds accordingto the invention. However, they are intended purely as examples ofmethods as an illustration of the invention without restricting it tothe subject matter described below by way of example.

EXAMPLE 16-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-oneHydrochloride

a) 1-(5-benzyloxy-2-hydroxy-3-nitrophenyl)-ethanone

18 mL fuming nitric acid are added dropwise to a solution of 81.5 g(0.34 mol) 1-(5-benzyloxy-2-hydroxyphenyl)-ethanone in 700 mL aceticacid while cooling with the ice bath, so that the temperature does notexceed 20° C. Then the reaction mixture is stirred for two hours atambient temperature, poured onto ice water and filtered. The product isrecrystallized from isopropanol, suction filtered and washed withisopropanol and diisopropylether. Yield: 69.6 g (72%); mass spectroscopy[M+H]⁺=288.

b) 1-(3-amino-5-benzyloxy-2-hydroxyphenyl)-ethanone

69.5 g (242 mmol) 1-(5-benzyloxy-2-hydroxy-3-nitrophenyl)-ethanone aredissolved in 1.4 L methanol and hydrogenated in the presence of 14 grhodium on charcoal (10%) as catalyst at 3 bar and ambient temperature.Then the catalyst is filtered off and the filtrate is evaporated down.The residue is reacted further without additional purification. Yield:60.0 g (96%), R_(f) value=0.45 (dichloromethane on silica gel).

c) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one

21.0 mL (258 mmol) chloroacetyl chloride are added dropwise to 60.0 g(233 mmol) 1-(3-amino-5-benzyloxy-2-hydroxyphenyl)-ethanone and 70.0 g(506 mmol) potassium carbonate while being cooled with the ice bath.Then the mixture is stirred overnight at ambient temperature and thenfor 6 hours at reflux temperature. The hot reaction mixture is filtered,then evaporated down to approx. 400 mL and combined with ice water. Theprecipitate obtained is suction filtered, dried and purified bychromatography on a short silica gel column(dichloromethane:methanol=99:1). The fractions containing the productare evaporated down, suspended in isopropanol/diisopropylether, suctionfiltered and washed with diisopropylether. Yield: 34.6 g (50%); massspectroscopy [M+H]⁺=298.

d) 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one

13.8 g (46.0 mmol) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one and35.3 g (101.5 mmol) benzyltrimethylammonium-dichloriodate are stirred in250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5hours at 65° C. After cooling to ambient temperature the mixture iscombined with 5% sodium hydrogen sulfite solution and stirred for 30minutes. The precipitated solid is suction filtered, washed with waterand diethyl ether and dried. Yield: 13.2 g (86%); mass spectroscopy[M+H]⁺=330/32.

e)6-benzyloxy-8-((R)-2-chloro-1-hydroxyethyl)-4H-benzo[1,4]-oxazin-3-one

The method is carried out analogously to a process described in theliterature (Org. Lett. 2002, 4, 4373-4376). 8 mL of a mixture of formicacid and triethylamine (molar ratio=5:2) are added dropwise at −15° C.to 13.15 g (39.6 mmol)6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one and 25.5 mg(0.04 mmol) Cp*RhCl[(S,S)-TsDPEN] (Cp*=pentamethylcyclopentadienyl andTsDPEN=(1S,2S)—N-p-toluenesulfonyl-1,2-diphenylethylenediamine) in 40 mLdimethylformamide. The mixture is stirred for 5 hours at thistemperature, then 25 mg catalyst are added and the mixture is stirredovernight at −15° C. The reaction mixture is combined with ice water andfiltered. The filter residue is dissolved in dichloromethane, dried withsodium sulfate and freed from the solvent. The residue ischromatographed (dichloromethane/methanol gradient) and the productrecrystallized from diethyl ether/diisopropylether. Yield: 10.08 g(76%); R_(f) value=0.28 (dichloromethane:methanol=50:1 on silica gel).

f) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one

10.06 g (30.1 mmol)6-benzyloxy-8-((R)-2-chloro-1-hydroxyethyl)-4H-benzo[1,4]-oxazin-3-oneare dissolved in 200 mL dimethylformamide. The solution is combined at0° C. with 40 mL of a 2 molar sodium hydroxide solution and stirred atthis temperature for 4 hours. The reaction mixture is poured onto icewater, stirred for 15 minutes and then filtered. The solid is washedwith water and dried. Yield: 8.60 g (96%); mass spectroscopy [M+H]⁺=298.

g)6-benzyloxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one

5.25 g (17.7 mmol) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-oneand 6.30 g (35.1 mmol) 2-(4-methoxyphenyl)-1,1-dimethylethylamine arecombined with 21 mL isopropanol and stirred for 30 minutes at 135° C.under microwave radiation in a closed reaction vessel. The solvent isdistilled off and the residue is chromatographed (aluminum oxide; ethylacetate/methanol gradient). The product thus obtained is furtherpurified by recrystallization from a diethyl ether/diisopropylethermixture. Yield: 5.33 g (63%); mass spectroscopy [M+H]⁺=477.

h)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-oneHydrochloride

A suspension of 5.33 g (11.2 mmol)6-benzyloxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-onein 120 mL methanol is combined with 0.8 g palladium on charcoal (10%),heated to 50° C. and hydrogenated at 3 bar hydrogen pressure. Then thecatalyst is suction filtered and the filtrate is evaporated down. Theresidue is dissolved in 20 mL isopropanol and 2.5 mL of 5 molarhydrochloric acid in isopropanol is added. The product is precipitatedwith 200 mL diethyl ether, suction filtered and dried. Yield: 4.50 g(95%, hydrochloride); mass spectroscopy [M+H]⁺=387.

The following compounds of formula 1 are obtained analogously byreacting the compound6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one (Example 1, Step f)with the corresponding amine.

EXAMPLE 28-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneHydrochloride

mass spectroscopy [M+H]⁺=393.

EXAMPLE 38-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneHydrochloride

mass spectroscopy [M+H]⁺=393.

EXAMPLE 48-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneHydrochloride

mass spectroscopy [M+H]⁺=401.

EXAMPLE 58-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneHydrochloride

mass spectroscopy [M+H]⁺=375.

If in some cases the compounds of formula 1 according to the method ofsynthesis described by way of example hereinbefore do not lead touniform crystal modifications, it may be useful to crystallize the saltsof formula 1 obtained from suitable solvents. In addition, other saltsmay be obtained from the foregoing Examples by using methods known perse in the art.

In the next section some exemplary methods of preparing uniform salts ofthe compounds of formula 1 which are particularly suitable for thepreparation of inhalable formulations will be described.

EXAMPLE 66-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-oneMaleate

250 mg (0.65 mmol)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-oneare combined with enough ethanol to make the solid dissolve completely.Then 75 mg (0.65 mmol) maleic acid and a crystallization aid are added.The mixture is cooled with ice and the precipitated solid is filteredoff and washed with ethanol and diethyl ether. In the salt the acid andthe ethanolamine are present in the ratio 1:1. Yield: 254 mg (78%); massspectroscopy [M+H]⁺=387; melting point=215° C.

The highly crystalline product was further investigated by X-ray powderdiffraction. The X-ray powder diagram was recorded as follows. The X-raypowder diagram was recorded within the scope of the present inventionusing a Bruker D8 Advanced with an location sensitive detector (LSD)(CuK_(α)—radiation, λ=1.5418 Å, 30 kV, 40 mA).

For the highly crystalline compound the following characteristic valuesd_(hkl) [Å], which give the lattice plane distances measured in Å, weredetermined, inter alia: d=21.68 Å; 8.62 Å; 5.92 Å; 5.01 Å; 4.59 Å; 4.36Å; 3.64 Å and 3.52 Å.

EXAMPLE 76-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-oneSalicylate

250 mg (0.65 mmol)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-oneare dissolved in a little ethanol and combined with 90 mg (0.65 mmol)salicylic acid. After the addition of a crystallization aid the mixtureis left to stand overnight, during which time a solid is precipitated.Diethyl ether is added and the mixture is filtered after 30 minutes. Thewhite solid thus obtained is washed with diethyl ether and dried. Yield:295 mg (87%); mass spectroscopy [M+H]⁺=387; melting point=215° C.

The highly crystalline product was further investigated by X-ray powderdiffraction. The X-ray powder diagram was recorded as follows. The X-raypowder diagram was recorded within the scope of the present inventionusing a Bruker D8 Advanced with a location sensitive detector (LSD)(CuK_(α)—radiation, λ=1.5418 Å, 30 kV, 40 mA).

For the highly crystalline compound the following characteristic valuesd_(hkl) [Å], which give the lattice plane distances measured in Å, weredetermined, inter alia: d=9.06 Å; 8.36 Å; 8.02 Å; 6.84 Å; 6.73 Å; 4.48Å; 4.35 Å and 4.27 Å.

EXAMPLE 86-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-oneSuccinate

500 mg (1.2 mmol)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-onehydrochloride are combined with ethyl acetate and extracted with aqueouspotassium carbonate solution, the organic phase is dried with sodiumsulfate and freed from the solvent. The residue is dissolved in a littleethanol and combined with 140 mg (1.2 mmol) succinic acid. After 2 hoursthe precipitated solid is suction filtered and washed with cold ethanoland diethyl ether. In the salt the ethanolamine and acid are present ina ratio of 1 to 0.5. Yield: 468 mg (85%); mass spectroscopy [M+H]⁺=387;melting point=115° C.

The highly crystalline product was further investigated by X-ray powderdiffraction. The X-ray powder diagram was recorded as follows. The X-raypowder diagram was recorded within the scope of the present inventionusing a Bruker D8 Advanced with a location sensitive detector (LSD)(CuK_(α)—radiation, λ=1.5418 Å, 30 kV, 40 mA).

For the highly crystalline compound the following characteristic valuesd_(hkl) [Å], which give the lattice plane distances measured in Å, weredetermined, inter alia: d=14.35 Å; 8.49 Å; 7.37 Å; 7.25 Å; 5.47 Å; 4.78Å; 4.14 Å and 3.59 Å.

EXAMPLE 96-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one-fumarate

300 mg (0.71 mmol)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-onehydrochloride are combined with ethyl acetate and extracted with aqueouspotassium carbonate solution. The organic phase is dried with sodiumsulfate and freed from the solvent. The residue is dissolved in ethanolwith the addition of a few drops of water. 82 mg (0.71 mmol) fumaricacid and seed crystals are added and the mixture is left to standovernight. The white solid is suction filtered, washed with diethylether and ethanol and dried. In the salt the ethanolamine and the acidare present in a ratio of 1 to 0.5. Yield: 208 mg (63%); massspectroscopy [M+H]⁺=387; melting point=130° C.

The highly crystalline product was further investigated by X-ray powderdiffraction. The X-ray powder diagram was recorded as follows. The X-raypowder diagram was recorded within the scope of the present inventionusing a Bruker D8 Advanced with a location sensitive detector (LSD)(CuK_(α)—radiation, λ=1.5418 Å, 30 kV, 40 mA).

For the highly crystalline compound the following characteristic valuesd_(hkl) [Å], which give the lattice plane distances measured in Å, weredetermined, inter alia: d=14.23 Å; 5.44 Å; 4.76 Å; 4.57 Å; 4.26 Å; 4.12Å; 3.57 Å and 3.48 Å.

EXAMPLE 106-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one(Free Base)

Analogously to the preceding methods 500 mg (1.2 mmol)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-onehydrochloride are first of all combined with ethyl acetate. The organicphase is extracted with aqueous potassium carbonate solution, dried withsodium sulfate and freed from the solvent. The free base thus obtainedis dissolved in acetonitrile with the addition of a few drops of water.The precipitated solid is suction filtered, washed and dried. Yield: 168mg (37%); mass spectroscopy [M+H]⁺=387; melting point=128° C.

The highly crystalline product was further investigated by X-ray powderdiffraction. The X-ray powder diagram was recorded as follows. The X-raypowder diagram was recorded within the scope of the present inventionusing a Bruker D8 Advanced with a location sensitive detector (LSD)(CuK_(α)—radiation, λ=1.5418 Å, 30 kV, 40 mA).

For the highly crystalline compound the following characteristic valuesd_(hkl) [Å], which give the lattice plane distances measured in Å, weredetermined, inter alia: d=14.96 Å; 9.63 Å; 7.05 Å; 5.57 Å; 5.28 Å; 5.05Å; 4.63 Å and 3.73 Å.

EXAMPLE 116-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-one-hydrochloride

300 mg (0.71 mmol)6-hydroxy-8-{(R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4,]oxazin-3-onehydrochloride are dissolved in 4 mL isopropanol by heating. The solutionis cooled to ambient temperature and then placed in an ice bath for 15minutes. The precipitated solid is suction filtered and dried. Yield:180 mg (60%); mass spectroscopy [M+H]⁺=387; melting point=211° C.

The highly crystalline product was further investigated by X-ray powderdiffraction. The X-ray powder diagram was recorded as follows. The X-raypowder diagram was recorded within the scope of the present inventionusing a Bruker D8 Advanced with an LSD (=location sensitive detector)(CuK_(α)—radiation, λ=1.5418 Å, 30 kV, 40 mA).

For the highly crystalline compound the following characteristic valuesd_(hkl) [Å], which give the lattice plane distances measured in Å, weredetermined, inter alia: d=5.92 Å; 5.81 Å; 5.51 Å; 5.10 Å; 4.65 Å; 4.50Å; 4.15 Å and 4.00 Å.

Using the method described in Examples 6 to 11 the following compoundsmay be obtained analogously:

EXAMPLE 128-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneMaleate EXAMPLE 138-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSalicylate EXAMPLE 148-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSuccinate EXAMPLE 158-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneFumarate EXAMPLE 168-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneMaleate EXAMPLE 178-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onesalicylate EXAMPLE 188-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSuccinate EXAMPLE 198-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneFumarate EXAMPLE 208-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneMaleate EXAMPLE 218-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSalicylate EXAMPLE 228-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSuccinate EXAMPLE 238-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneFumarate EXAMPLE 248-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneMaleate EXAMPLE 258-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSalicylate EXAMPLE 268-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneSuccinate EXAMPLE 278-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneFumarate EXAMPLE 288-{(R)-2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one(Free Base) EXAMPLE 298-{(R)-2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one(Free Base) EXAMPLE 308-{(R)-2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one(Free Base) or EXAMPLE 318-{(R)-2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one(Free Base)

The compounds of general formula 1 may be used on their own or inconjunction with other active substances of formula 1 according to theinvention. If desired the compounds of general formula 1 may also beused in conjunction with other pharmacologically active substances.Preferably the present invention also relates to drug combinations whichcontain in addition to one or more, preferably one compound of formula1, as an additional active substance one or more compounds selected fromthe categories of the anticholinergics, PDEIV inhibitors, steroids,LTD4-antagonists and EGFR inhibitors.

Anticholinergics are preferably used, while compounds selected frombromides and chlorides of the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium and trospium are of particularinterest. Of particular importance is tiotropium bromide, preferably inthe form of crystalline tiotropium bromide monohydrate, which is knownfrom WO 02/30928. If tiotropium bromide is used in the drug combinationsaccording to the invention in anhydrous form, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

In another preferred embodiment of the present invention theanticholinergic used is the compound

optionally in the form of the enantiomers thereof.

The following compounds are optionally also used as anticholinergics incombination with the compounds of formula 1:

-   -   tropenol 2,2-diphenylpropionate methobromide,    -   scopine 2,2-diphenylpropionate methobromide,    -   scopine 2-fluoro-2,2-diphenylacetate methobromide,    -   tropenol 2-fluoro-2,2-diphenylacetate methobromide,    -   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,    -   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,    -   tropenol 4,4′-difluorobenzilate methobromide,    -   scopine 4,4′-difluorobenzilate methobromide,    -   tropenol 3,3′-difluorobenzilate methobromide,    -   scopine 3,3′-difluorobenzilate methobromide,    -   tropenol 9-hydroxyfluorene-9-carboxylate methobromide;    -   tropenol 9-fluorofluorene-9-carboxylate methobromide;    -   scopine 9-hydroxyfluorene-9-carboxylate methobromide;    -   scopine 9-fluorofluorene-9-carboxylate methobromide;    -   tropenol 9-methylfluorene-9-carboxylate methobromide;    -   scopine 9-methylfluorene-9-carboxylate methobromide;    -   cyclopropyltropine benzilate methobromide,    -   cyclopropyltropine 2,2-diphenylpropionate methobromide;    -   cyclopropyltropine 9-hydroxyxanthene-9-carboxylate methobromide;    -   cyclopropyltropine 9-methylfluorene-9-carboxylate methobromide;    -   cyclopropyltropine 9-methylxanthene-9-carboxylate methobromide;    -   cyclopropyltropine 9-hydroxyfluorene-9-carboxylate methobromide;    -   methyl cyclopropyltropine 4,4′-difluorobenzilate methobromide.    -   tropenol 9-hydroxyxanthene-9-carboxylate methobromide;    -   scopine 9-hydroxyxanthene-9-carboxylate methobromide;    -   tropenol 9-methylxanthene-9-carboxylate methobromide;    -   scopine 9-methylxanthene-9-carboxylate methobromide;    -   tropenol 9-ethylxanthene-9-carboxylate methobromide;    -   tropenol 9-difluoromethylxanthene-9-carboxylate methobromide; or    -   scopine 9-hydroxymethylxanthene-9-carboxylate methobromide.

If PDE IV inhibitors are used in combination with one or more compoundsof general formula 1, these are preferably selected from amongEnprofyllin, Theophyllin, Roflumilast, Ariflo (Cilomilast), CP-325,366,BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470),N-(3,5-dichloro-1-oxopyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,NCS-613, Pumafentine,(−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, Arofyllin,Atizoram, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997,Z-15370,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of their racemates, enantiomers or diastereomersand optionally in the form of their pharmacologically acceptable acidaddition salts, solvates and/or hydrates. By acid addition salts withpharmacologically acceptable acids are meant for example salts selectedfrom among the hydrochloride, hydrobromide, hydroiodide, hydrosulfate,hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate,hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide,hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.

If steroids are used in combination with one or more compounds ofgeneral formula 1, they are preferably selected from among prednisolone,prednisone, butixocortpropionate, RPR-106541, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, ST-126, dexamethasone, (S)-fluoromethyl6□,9□-difluoro-17□-[(2-furanylcarbonyl)oxy]-11□-hydroxy-16□-methyl-3-oxo-androsta-1,4-diene-17□-carbothionate,and(S)-(2-oxo-tetrahydro-furan-3S-yl)6□,9□-difluoro-11□-hydroxy-16□-methyl-3-oxo-17□-propionyloxy-androsta-1,4-diene-17□-carbothionate,optionally in the form of their racemates, enantiomers or diastereomersand optionally in the form of their salts and derivatives, the solvatesand/or hydrates thereof. Any reference to steroids includes a referenceto any salts or derivatives, hydrates or solvates thereof that mayexist. Examples of possible salts and derivatives of the steroids maybe: alkali metal salts, such as for example sodium or potassium salts,sulfobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogenphosphates, palmitates, pivalates or furoates.

If LTD4-antagonists are used in combination with one or more compoundsof general formula 1, these are preferably selected from amongmontelukast,1-(((R)-(3-(2-(6.7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid,1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridine-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropanaceticacid, pranlukast, zafirlukast,[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078,VUF-K-8707 and L-733321, optionally in the form of their racemates,enantiomers or diastereomers, optionally in the form of theirpharmacologically acceptable acid addition salts as well as optionallyin the form of their salts and derivatives, the solvates and/or hydratesthereof. By acid addition salts with pharmacologically acceptable acidswhich the LTD4-antagonists may be capable of forming are meant, forexample, salts selected from among hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate,hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride,hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate andhydromethanesulfonate. By salts or derivatives which theLTD4-antagonists, may be capable of forming are meant, for example:alkali metal salts, such as for example sodium or potassium salts,alkaline earth metal salts, sulfobenzoates, phosphates, isonicotinates,acetates, propionates, dihydrogen phosphates, palmitates, pivalates orfuroates.

If EGFR inhibitors are used in combination with one or more compounds ofgeneral formula 1, they are preferably selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxyethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methanesulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazolineand4-[(3-chloro-4-fluorophenyl)amino]-6-(1-cyanopiperidin-4-yloxy)-7-methoxy-quinazoline,optionally in the form of their racemates, enantiomers or diastereomers,optionally in the form of their pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned EGFR inhibitors might be capable of forming are meant,for example, salts selected from among hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate,hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride,hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate andhydromethanesulfonate.

Suitable preparations for administering the compounds of formula 1include tablets, capsules, suppositories, solutions, powders, etc. Theproportion of pharmaceutically active compound or compounds should be inthe range from 0.05 to 90% by weight, preferably 0.1 to 50% by weight ofthe total composition. Suitable tablets may be obtained, for example, bymixing the active substance(s) with known excipients, for example inertdiluents such as calcium carbonate, calcium phosphate or lactose,disintegrants such as corn starch or alginic acid, binders such asstarch or gelatin, lubricants such as magnesium stearate or talc and/oragents for delaying release, such as carboxymethyl cellulose, celluloseacetate phthalate, or polyvinyl acetate. The tablets may also compriseseveral layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, arabic gum, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinations ofactive substances according to the invention may additionally contain asweetener such as saccharine, cyclamate, glycerol or sugar and a flavorenhancer, e.g., a flavoring such as vanillin or orange extract. They mayalso contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

Solutions are prepared in the usual way, e.g., with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates, orstabilizers such as alkali metal salts of ethylenediamine tetraaceticacid, optionally using emulsifiers and/or dispersants, whilst if wateris used as the diluent, for example, organic solvents may optionally beused as solvating agents or dissolving aids, and transferred intoinjection vials or ampoules or infusion bottles.

Capsules containing the compounds of formula 1 according to theinvention may for example be prepared by mixing the active substanceswith inert carriers such as lactose or sorbitol and packing them intogelatin capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as, e.g., natural mineral powders (e.g., kaolins, clays, talc,chalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose and glucose),emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose,starch and polyvinylpyrrolidone) and lubricants (e.g., magnesiumstearate, talc, stearic acid and sodium lauryl sulfate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatin and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulfate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavor enhancers or colorings in addition to the excipients mentionedabove.

When the compounds of formula 1 are used, as is particularly preferredaccording to the invention, for the treatment of respiratory complaints,it is particularly preferable to use preparations or pharmaceuticalformulations that can be administered by inhalation. Suitableformulations for inhalation include inhalable powders, propellant-drivenmetered-1-dose aerosols or propellant-free inhalable solutions. Withinthe scope of the present invention the term propellant-free inhalablesolutions also includes concentrates or sterile ready-to-use inhalablesolutions.

The compounds of formula 1 which are particularly preferably used incrystalline form according to the invention are preferably used forpreparing inhalable powders. The inhalable powders which may be usedaccording to the invention may contain the crystalline compounds offormula 1 either on their own or in admixture with suitablephysiologically acceptable excipients.

If the active substances are present in admixture with physiologicallyacceptable excipients, the following physiologically acceptableexcipients may be used to prepare these inhalable powders according tothe invention: monosaccharides (e.g., glucose or arabinose),disaccharides (e.g., lactose, saccharose, maltose), oligo- andpolysaccharides (e.g., dextrans), polyalcohols (e.g., sorbitol,mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate) ormixtures of these excipients. Preferably, mono- or disaccharides areused, while the use of lactose or glucose is preferred, particularly,but not exclusively, in the form of their hydrates. For the purposes ofthe invention, lactose is the particularly preferred excipient, whilelactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.In some cases it may seem appropriate to add finer excipient fractionswith an average particle size of 1 to 9 μm to the excipient mentionedabove. These finer excipients are also selected from the group ofpossible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronized activesubstance, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micron sing and finally mixing the ingredients togetherare known from the prior art.

The inhalable powders according to the invention may be administeredusing inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain dissolved in the propellant gas or in dispersedform. The propellant gases which may be used to prepare the inhalationaerosols are known from the prior art. Suitable propellant gases areselected from among hydrocarbons such as n-propane, n-butane orisobutane and halohydrocarbons such as fluorinated derivatives ofmethane, ethane, propane, butane, cyclopropane or cyclobutane. Theabove-mentioned propellant gases may be used on their own or inadmixture. Particularly preferred propellant gases are halogenatedalkane derivatives selected from TG134a and TG227 and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co-solvents, stabilizers, surfactants, antioxidants,lubricants and pH adjusters. All these ingredients are known in the art.

The propellant-driven inhalation aerosols according to the inventionmentioned above may be administered using inhalers known in the art(MDIs=metered dose inhalers).

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation the compounds of theformula are characterized by a high potency even at doses in the μgrange. The compounds of the formula may also be used effectively abovethe μg range. The dosage may then be in the milligram range, forexample.

In another aspect the present invention relates to the above-mentionedpharmaceutical formulations, characterized in that they contain acompound of formula 1, as such, particularly preferably theabove-mentioned pharmaceutical formulations for use by inhalation.

The following formulation examples illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

D) Metering aerosol Active substance 0.005 Sorbitan trioleate 0.1TG134a:TG227 2:1 ad 100

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μl of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g., 0.02% by weight).

E) Solutions (in mg/100 mL) Active substance 333.3 mg Benzalkoniumchloride 10.0 mg EDTA 50.0 mg HCl (1N) ad pH 3.4

This solution may be prepared in the usual manner.

F) Powder for inhalation Active substance 12 μg Lactose monohydrate ad25 mg

The powder for inhalation is produced in the usual way by mixing theindividual ingredients together.

1-12. (canceled)
 13. A method for the treatment of respiratorycomplaints comprising administering to a patient a therapeuticallyeffective amount ofR-6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-onehydrochloride.
 14. The method according to claim 13, wherein thetreatment is once-a-day.
 15. The method according to claim 13, whereinsaid respiratory complaint is COPD (chronic obstructive pulmonarydisease).
 16. The method according to claim 15, wherein the treatment isonce-a-day.
 17. The method according to claim 13, wherein saidrespiratory complaint is asthma.
 18. The method according to claim 17,wherein the treatment is once-a-day.
 19. The method according to claim13, wherein said respiratory complaints are selected from the groupconsisting of bronchial asthma, pediatric asthma, severe asthma, acuteasthma attacks and chronic bronchitis.
 20. The method according to claim19, wherein the treatment is once-a-day.
 21. A method for the treatmentof respiratory complaints comprising administering to a patient atherapeutically effective amount ofR-8-{2-[2-(2,4-Difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehydrochloride.
 22. The method according to claim 21, wherein thetreatment is once-a-day.
 23. The method according to claim 21, whereinsaid respiratory complaint is COPD (chronic obstructive pulmonarydisease).
 24. The method according to claim 23, wherein the treatment isonce-a-day.
 25. The method according to claim 21, wherein saidrespiratory complaint is asthma.
 26. The method according to claim 25,wherein the treatment is once-a-day.
 27. The method according to claim21, wherein said respiratory complaints are selected from the groupconsisting of bronchial asthma, pediatric asthma, severe asthma, acuteasthma attacks and chronic bronchitis.
 28. The method according to claim27, wherein the treatment is once-a-day.
 29. A method for the treatmentof respiratory complaints comprising administering to a patient atherapeutically effective amount ofR-8-{2-[2-(3,5-Difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehydrochloride.
 30. The method according to claim 29, wherein thetreatment is once-a-day.
 31. The method according to claim 29, whereinsaid respiratory complaint is COPD (chronic obstructive pulmonarydisease).
 32. The method according to claim 31, wherein the treatment isonce-a-day.
 33. The method according to claim 29, wherein saidrespiratory complaint is asthma.
 34. The method according to claim 33,wherein the treatment is once-a-day.
 35. The method according to claim29, wherein said respiratory complaints are selected from the groupconsisting of bronchial asthma, pediatric asthma, severe asthma, acuteasthma attacks and chronic bronchitis.
 36. The method according to claim35, wherein the treatment is once-a-day.
 37. A method for the treatmentof respiratory complaints comprising administering to a patient atherapeutically effective amount ofR-8-{2-[2-(4-Ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehydrochloride.
 38. The method according to claim 37, wherein thetreatment is once-a-day.
 39. The method according to claim 37, whereinsaid respiratory complaint is COPD (chronic obstructive pulmonarydisease).
 40. The method according to claim 39, wherein the treatment isonce-a-day.
 41. The method according to claim 37, wherein saidrespiratory complaint is asthma.
 42. The method according to claim 41,wherein the treatment is once-a-day.
 43. The method according to claim37, wherein said respiratory complaints are selected from the groupconsisting of bronchial asthma, pediatric asthma, severe asthma, acuteasthma attacks and chronic bronchitis.
 44. The method according to claim43, wherein the treatment is once-a-day.
 45. A method for the treatmentof respiratory complaints comprising administering to a patient atherapeutically effective amount ofR-8-{2-[2-(4-Fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehydrochloride
 46. The method according to claim 45, wherein thetreatment is once-a-day.
 47. The method according to claim 45, whereinsaid respiratory complaint is COPD (chronic obstructive pulmonarydisease).
 48. The method according to claim 47, wherein the treatment isonce-a-day.
 49. The method according to claim 45, wherein saidrespiratory complaint is asthma.
 50. The method according to claim 49,wherein the treatment is once-a-day.
 51. The method according to claim45, wherein said respiratory complaints are selected from the groupconsisting of bronchial asthma, pediatric asthma, severe asthma, acuteasthma attacks and chronic bronchitis.
 52. The method according to claim51, wherein the treatment is once-a-day.